PROJECT SUMMARY Aortic elasticity creates a Windkessel effect. That is, aortas distend following ejection of blood from the left ventricle (LV) during systole, and then recoil after aortic valve closure. This feature of ventricular-arterial coupling blunts peak blood pressure and flow waves providing a cushioning effect that protects the heart from pressure injury. In addition, the Windkessel effect helps move blood distally through the coronary arteries and periphery during cardiac relaxation. Aortic stent-grafts are made of stiff materials that artificially stiffen the aorta and diminish the Windkessel effect. This may overwork the heart, eventually leading to pathological changes. While stiff stent-grafts are generally thought to work well in the aorta, the subtle long-term effects associated with stent-grafting may not be reported in the stent-graft literature that focuses primarily on mortality and local complications requiring re-intervention. Recent evidence from our team demonstrates that implantation of stiff thoracic aortic stent-grafts in young trauma patients is associated with significantly increased LV mass and wall thickness, and in pigs results in aortic stiffening and early LV fibrosis. Similar outcomes were recently reported in elderly patients with thoracic and abdominal aortic stent-grafts. In order to mitigate these effects and preserve aortic compliance, our team has developed a new elastomeric nanofibrillar aortic stent-graft that possesses aorta-like mechanical properties and microstructure, and is able to preserve aortic elasticity and the Windkessel effect, and maintain normal pressure waveforms as opposed to stiff conventional stent-grafts in vitro. Furthermore, in vivo our nanofibrillar material maintains its compliance, undergoes rapid endothelialization, and gets quickly incorporated into the arterial wall. We propose to test the hypothesis that preservation of aortic compliance with a new-generation compliant stent-graft results in normal hemodynamics and prevents cardiac and aortic pathologies. This hypothesis will be tested through 3 Specific Aims. In Aim 1 we will manufacture nanofibrillar elastomeric stent-grafts with tunable compliance. In Aim 2 we will quantify the effect of stent-graft compliance on Windkessel function in human and porcine aortas using an ex vivo flow model. Finally, in Aim 3 we will assess the in vivo effects of stent-graft compliance on hemodynamics and cardiac and aortic pathologies in a swine model. This will be done by comparing the effects of aortic compliance and Windkessel reduction on the heart and the aorta when using commercial stent-grafts versus devices made using stiff and compliant nanofibrillar materials. This project will quantify the effects of stiff stent-grafts on aortic compliance and cardiac pathophysiology, and will propose a new- generation stent-graft that protects the aorta and the heart from pathologic remodeling. While compliance is highest in young aortas, older patients with weaker hearts may be most sensitive to its alteration. Considering the ubiquitous use of stiff stent-grafts in patients of all ages, the clinical importance of better minimally-invasive aortic devices is difficult to overestimate.